This invention relates to a method of treating hemoglobinopathies utilizing polyhydroxybenzoic acid derivatives, such as polyhydroxybenz-amides, -hydroxamic acids, -amidoximes, -amidines, -amidates, -esters, as well as the corresponding polyhydroxyphenylacetic acid and polyhydroxymandelic acid derivatives, and compounds of related structure as the active pharmacologic agents.
Hemoglobinopathies encompass a number of anemias of genetic origin in which there is decreased production and/or increased destruction (hemolysis) of red blood cells (RBCs). The blood of normal adult humans contains hemoglobin (designated as HbA) which contains two pairs of polypeptide chains designated alpha and beta. Fetal hemoglobin (HbF), which produces normal RBCs, is present at birth, but the proportion of HbF decreases during the first months of life and the blood of a normal adult contains only about 2% HbF. There are genetic defects which result in the production by the body of abnormal hemoglobins with a concomitant impaired ability to maintain oxygen concentration. Among these genetically derived anemias are included thalassemia, Cooley's Disease and, most importantly, sickle-cell anemia (HbS disease).
Sickle-cell anemia is an inherited chronic hemolytic anemia characterized by sickle-shaped RBCs present in part of the offspring of parents who are both heterozygotes to the abnormal gene which causes the sickling disease. This disease is recessive, and heterozygotes carrying this gene show no blatant anemia or similar abnormality. Thus, only about 25% of the children of parents who are both heterozygous are expected to be homozygotic to this abnormal gene and will develop sickle cell anemia and eventually sickling crisis (aplastic crisis). Few homozygotes live past 40 years of age and may show abnormal body growth patterns. The gene which characterizes sickling trait causes valine to be substituted for glutamic acid in the sixth peptide of the beta chain, thus producing HbS rather than HbA. Deoxygenated HbS is much less soluble than deoxy HbA and it forms a semisolid gel of rodlike tactoids, thus causing the RBCs produced from HbS to assume a sickle shape. These abnormallyshaped RBCs form a sort of sludge. In addition, these HbS RBCs are more fragile than normal RBCs and hemolyze more easily, thus leading eventually to anemia.
The clinical manifestations of an aplastic crisis in sickle-cell homozygotes include arthralgia with fever, jaundice, aseptic necrosis of the femoral head, chronic punched-out ulcers about the ankles plus episodes of severe abdominal pain with vomiting. Thrombosis and/or infarction may also be present. Laboratory findings include a monocytic anemia with an RBC count in the range 2-3.times.10.sup.6.
Early death, usually before 40, is caused by intercurrent infections (especially tuberculosis), multiple pulmonary emboli or thrombosis of a vessel supplying a vital area.
In the past, treatment of sickle-cell anemia was symptomatic only. Recently, however, it has been found that drugs which can increase production of the normal fetal hemoglobin HbF ( since clearly, drugs cannot alter the HbS/HbA ratio in homozygotes since it is genetically determined), can tide a homozygote over the aplastic crisis, and thus potentially prolong their life. It has been known for some time that drugs such as 5-azacytidine, cytarabine and hydroxyurea could augment HbF production in anemic monkeys--see Levine et al, New Eng. J. Med. 310:869 (1984) and references cited therein. Recent limited clinical studies have shown that these drugs do indeed increase HbF production in patients with sickle-cell disease--see Goldberg et al, New Eng. J. Med. 323:366 (1990) for hydroxyurea; Charache, Dover and co-workers, Blood 69:109 (1988); 6th Annual Conf. on Hemoglobin Switching, Sep. 2, 1988 for 5-azacytidine and hydroxyurea; Veith et al, New Eng. J. Med. 313:1571 (1985) for cytarabine and hydroxyurea.
In addition to the previously cited experiments in anemic monkeys (Levin et al loc. cit.), more recently Constantoulakis et al, Blood 77:1326 (1991) have developed a new model system for studying the induction of fetal hemoglobin (HbF) by various drugs, using adult transgenic mice carrying the human A(gamma) globin gene linked to the locus control region regulatory sequences and expressing heterocellularly HbF. Erythropoietin, 5-azacytidine, hydroxyurea and butyric acid esters (butyrate), all known in vivo HbF inducers in adult humans, also induced HbF in this model.